6rlz
From Proteopedia
Crystal Structure of 14-3-3zeta in complex with a macrocyclic 8-mer peptide derived from ExoS
Structural highlights
Function1433Z_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.[1] [2] [3] [4] [5] Publication Abstract from PubMedLarge and flexible ligands gain increasing interest in the development of bioactive agents. They challenge the applicability of computational ligand optimization strategies originally developed for small molecules. Free energy perturbation (FEP) is often used for predicting binding affinities of small molecule ligands, however, its use for more complex ligands remains limited. Herein, we report the structure-based design of peptide macrocycles targeting the protein binding site of human adaptor protein 14-3-3. We observe a surprisingly strong dependency of binding affinities on relatively small variations in substituent size. FEP was performed to rationalize observed trends. To account for insufficient convergence of FEP, restrained calculations were performed and complemented with extensive REST MD simulations of the free ligands. These calculations revealed that changes in affinity originate both from altered direct interactions and conformational changes of the free ligand. In addition, MD simulations provided the basis to rationalize unexpected trends in ligand lipophilicity. We also verified the anticipated interaction site and binding mode for one of the high affinity ligands by X-ray crystallography. The introduced fully-atomistic simulation protocol can be used to rationalize the development of structurally complex ligands which will support future ligand maturation efforts. Adapting free energy perturbation simulations for large macrocyclic ligands: how to dissect contributions from direct binding and free ligand flexibility.,Wallraven K, Holmelin FL, Glas A, Hennig S, Frolov AI, Grossmann TN Chem Sci. 2020 Jan 22;11(8):2269-2276. doi: 10.1039/c9sc04705k. eCollection 2020 , Feb 28. PMID:32180932[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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